Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). These studies tend to be very long term with varying activity. Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues;in collaboration with an international consortium (GenoMEL), a search for a new melanoma susceptibility genes continues both within families and a genome-wide association study. In the American melanoma-prone families, we evaluated 1536 SNPs in 152 genes involved in DNA repair, apoptosis, and immune response pathways among 537 individuals from 28 families (19 CDKN2A+ and 9 CDKN2A -) to try to identify potential modifier genes. We found some differences in CDKN2A + and - families;several candidate genes appeared significant in gene-based tests;IL9 was significant after correction for multiple comparisone and may be of interest as a candidate modifier. We also investigated two other candidate genes of interest, CHD5 in 1p336 and PTPRD in 9p23-24.1 as major susceptibility genes;neither had inherited mutations in these families. We continue to accrue and evaluate new families in both the U.S and Italy. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma.<BR;BR;BR;BR>The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. With linkage analyses showing evidence of linkage in a different chromosomal area last year, we have extensively investigated genes in the region. Analyses are ongoing.<BR;BR;BR;BR>Studying families with lymphoproliferative cancers has been a long-standing interest. We used the same Illumina custom platform of 1536 SNPs in 152 genes as in the melanoma study to evaluate the genes and pathways among 165 unrelated familial cases with CLL, Waldenstrom macroglobulinemia (WM), or Hodgkin lymphoma (HL) and 107 spouse controls. We found that a polymorphism in IL10 promoter was associated with both CLL and WM and vairations in IL6 were associated with HL. We also collaborated with extramural investigators in evaluating one of our large families with a reciprocal translocation that disrupts KLHDC8B. We then tested KLHDC8B as a condidate gene in other families and found that a 5'UTR polymorphism is associated with HL in other families, cosegregates with disease, and had LOH in Reed Sternberg cells from one case. In addition, depletion of KLHDC8B by RNA interference led to binucleated cells. <BR;BR;BR;BR>We have continued working with the Urologic Oncology Branch in the evaluation of families with renal cancers. In families with fumarate hydratase mutations with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) in North America, we evaluated the risk factors for uterine leiomyomas. Women in these families had high rates of hysterectomy before age 30 for multiple uterine leiomyomas. Risk of developing leiomyomas was much higher in individuals either clinically affected with HLRCC or with mutations in FH. We also continued a family study of Xeroderma pigmentosum in collaboration with CCR investigators to assess risk of cancer in XP heterozygotes. Data collection is underway. We have also documented that mothers carrying affected children with tricothiodystrophy have more pregnancy complications than when carrying unaffected children.